tbuckley/cabot-search huggingface dataset:
CTNI-71. BELZUTIFAN FOR VON HIPPEL-LINDAU DISEASE-RELATED CENTRAL NERVOUS SYSTEM (CNS) HEMANGIOBLASTOMAS: SUBGROUP OF PHASE 2 LITESPARK-004 STUDY
Authors: Othon Iliopoulos, Ane B Iversen, Vivek Narayan, Benjamin L Maughan, Kathryn E Beckermann, Stephane Oudard, Tobias Else, Jodi K Maranchie, Wei Fu, Rodolfo F Perini, Yanfang Liu, W Marston Linehan, Srinivasan Srinivasan, Eric Jonasch
Journal: Neuro-Oncology (2023)

Abstract The HIF-2α inhibitor belzutifan is approved for von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC), CNS hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery based on results of the phase 2 LITESPARK-004 study (NCT03401788). Updated results in patients with CNS hemangioblastomas are presented. Adults with VHL disease based on germline VHL alteration, ≥ 1 measurable RCC tumor, and no prior systemic anticancer therapy received oral belzutifan 120 mg once daily. End points included ORR, DOR, and PFS per RECIST v1.1 and safety. CNS hemangioblastomas were assessed using 2 approaches: (1) measurable (≥ 1 cm) and/or nonmeasurable lesions at baseline based on total size of solid and associated cystic components, if present, and (2) only measurable solid lesions at baseline. Of 61 patients, 50 (82%) had ≥ 1 CNS hemangioblastoma evaluable at baseline; 19/50 (38%) underwent ≥ 1 CNS-related procedure ≤ 3 years before starting belzutifan. Median follow-up was 38.0 months (range, 36.1-46.1). ORR was 44%. Median DOR was not reached (NR; range, 3.7+ to 38.7+ months). DCR was 90%. Median PFS was NR (95% CI, 38 months-NR). 25/50 (50%) had ≥ 1 measurable, solid-only CNS hemangioblastoma. For these patients, ORR was 76%. Median DOR was NR (range, 3.7+ to 38.7+ months). DCR was 96%. Median PFS was NR (95% CI, 36 months-NR). 2/50 patients (4%) underwent 3 procedures for CNS hemangioblastomas after starting treatment with belzutifan. Two patients (3%) discontinued treatment due to treatment-related AEs (grade 2 intracranial hemorrhage and grade 1 dizziness). RESULTS: showed consistent and durable antitumor activity in patients with CNS hemangioblastomas. Belzutifan induced shrinkage of CNS hemangioblastomas with or without the presence of associated cysts. © 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting. All rights reserved.
SURG-08. THE CLEARPOINT ARRAY® FRAME: A NOVEL MRI COMPATIBLE SYSTEM THAT SUPPORTS NON-CRANIOTOMY, MULTI-TRAJECTORY (NCMT) STEREOTACTIC PROCEDURES
Authors: Youssef Hamade, Clark Chen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND With continued evolution in stereotactic techniques and an expanding armamentarium of therapeutic options, non-craniotomy stereotactic procedures in neuro-oncology are becoming increasingly complex, often requiring multi-trajectory approaches. Here we demonstrate that the ClearPoint SmartFrame Array®, a second-generation MRI-compatible stereotactic frame, supports such non-craniotomy, multi-trajectory (NCMT) stereotactic procedures. METHODS Through a case report, we previously established the feasibility of NCMT through the ClearPoint SmartFrame Array®. Here we prospectively followed the next ten consecutive patients who underwent such multi-trajectory procedures to establish procedural safety and clinical utility. RESULTS Ten patients underwent complex, multi-trajectory stereotactic procedures, including combinations of needle biopsy + cyst drainage and laser interstitial thermal therapy (LITT) targeting geographically distinct regions of neoplastic lesions under the same anesthetic event. For each intended target, the maximal radial error of stereotaxis ranged 0.1-2.7 mm (with a median of 1.0 mm). In all cases, definitive diagnosis was achieved, and &amp;gt;90% of the intended targets were ablated. The average stereotaxis time (time required to establish the trajectories) for the multi-trajectory procedure was 119 + 22.2 minutes, which is not statistically different from our published results for single-trajectory procedures (80 + 9.59 minutes, p = 0.125). There were no procedural complications. Post-procedure, the neurologic condition of one patient improved, while the remaining nine patients remained stable. All patients were discharged home, with a median hospital stay of one day (range: 1-12 days). With a median follow-up of 376 days (range: 155-1438 days), there were no 30-day readmission or wound complications. There were two 90-day readmissions (a patient with hydrocephalus and another with new spine metastasis) unrelated to the procedures performed. CONCLUSION Geographically distinct regions of a brain cancer can be safely and accurately accessed through the ClearPoint Array® frame in NCMT stereotactic procedures.
DDDR-15. RESISTANCE TO TARGETED ANTI-MITOTICS IN GLIOBLASTOMA IS DRIVEN BY STAT3 ACTIVATION AND THERAPY INDUCED SENESCENCE
Authors: Rajappa Kenchappa, Natanael Zarco, Athanassios Dovas, Michael Argenziano, Ashley Haddock, Peter Canoll, Steven Rosenfeld
Journal: Neuro-Oncology (2023)

Abstract Tumor cells require the mitotic spindle to drive chromosome separation in metaphase, which has made the spindle a compelling target for development of anti-mitotics. However, most of these spindle inhibitors target microtubules and can thereby be highly neurotoxic. This has motivated development of targeted anti-mitotics that inhibit non-microtubule components of the spindle, including kinesins and mitotic kinases. These drugs are not neurotoxic and prolong survival in tumor patients, but resistance limits their efficacy. We reported (Kenchappa et al., Cell Reports, 2022) that resistance to one of these—ispinesib, a highly specific inhibitor of the mitotic kinesin Kif11—requires two functions of STAT3: activation of transcription in the nucleus and of oxidative phosphorylation in the mitochondria. Inhibiting both functions reverses ispinesib resistance. Furthermore, combining ispinesib with a CNS-permeant STAT3 inhibitor significantly prolongs survival over ispinesib alone in both immunocompetent and PDX GBM models. We now report that resistance to two other targeted anti-mitotics—alisertib (Aurora Kinase inhibitor) and volasertib (Polo Like Kinase inhibitor)—works similarly and can likewise be reversed with STAT3 inhibitors. For all three of these anti-mitotics, resistance goes hand-in-hand with development of therapy-induced senescence (TIS) in approximately half of GBM cells. TIS cells secrete a variety of soluble factors, referred to as the senescence associated secretory phenotype (SASP), which stimulate stemness, angiogenesis, and immunosuppression. We propose that: 1) TIS cells require STAT3 for survival, and that they in turn maintain a drug resistant state by suppressing mitosis in the remaining, non senescent cells through components of the SASP; and 2) by killing TIS cells, STAT3 inhibitors restore anti-mitotic sensitivity in the remaining, non-senescent tumor cells. We propose that this STAT3/TIS model of resistance may also apply to how resistance develops to other GBM therapies, and may guide similar translational approaches to enhancing therapeutic efficacy.
BIOM-62. DETECTION OF EXCLUSIVE MUTATIONS AND GENE-GENE FUSIONS IN GLIOBLASTOMA THROUGH ANALYSIS OF CIRCULATING CELL-FREE DNA (CFDNA) AS AN EMERGING DIAGNOSTIC TOOL
Authors: Milana Frenkel-Morgenstern, Olawumi Giwa, Eliezer Gideon Baum, Andrew Kaner, Yossef Laviv, Sagi Har Nof, Adva Levy-Barda, Tali Siegal
Journal: Neuro-Oncology (2023)

Abstract Tumor heterogeneity is a significant obstacle for developing tailored therapies for glioblastoma (GBM). We collected blood and tumors from 20 GBM patients at 4-time points and 20 blood samples from healthy controls. cfDNA was extracted from the plasma of GBM patients and healthy controls. Tumor DNA was extracted from fresh tumor samples. Extracted DNA was sequenced using a whole-genome sequencing procedure. We found that plasma cfDNA concentrations in GBM patients were significantly elevated (22.6 ± 5 ng·mL-1), as compared to healthy controls (1.4 ± 0.4 ng·mL-1). We identified unique mutations in cfDNA of GBM patients, including some of the most frequently mutated genes in GBM (TP53, 18.75%; EGFR, 37.5%; NF1, 12.5%; LRP1B, 25%; IRS4, 25%) and built a unique clinical panel for further patients monitoring. Using our gene fusion database, ChiTaRS 5.0, we identified gene fusions in both tumor DNA and cfDNA, such as KDR-PDGFRA and NCDN-PDGFRA, which correspond to previously reported alterations of PDGFRA in GBM (44% of all samples). Interestingly, the PDGFRA protein fusions can be targeted by tyrosine kinase inhibitors. We identified ROS1 fusions (CEP85L-ROS1 and GOPC-ROS1) in 8% of samples, and those might be targeted by crizotinib analogs. Moreover, we analyzed TCGA/ICGC data of 180 GBM samples and observed FGFR3-TACC3, EGFR-SEPT14 fusions in silico. Next, we measured cfDNA levels in vitro in response to Temozolomide treatment and discovered a positive correlation between unique 2000bp cfDNA fragments (R = 0.8961, P-value = 0.015632) and treatment responses in vitro. We extracted exosomes from the in-vitro experiments and validated the concentrations of both the encapsulated cfDNA as well as the free cfDNA. We found that half of cfDNA was exosome encapsulated and it varied according to the tumor stage. CONCLUSION: cfDNA may be used for the detection of exclusive patient mutations and gene fusions and is an emerging diagnostic tool in GBM.
NCMP-18. ENDOVASCULAR TREATMENT OF SYMPTOMATIC TUMORAL VENOUS SINUS STENOSIS: COMPARATIVE ANALYSIS OF CORONARY BALLOON-MOUNTED STENTS AND CONVENTIONAL TECHNIQUES
Authors: Adrian Chen, Sabrina Begley, Timothy G White
Journal: Neuro-Oncology (2023)

Abstract Meningiomas may lead to symptomatic papilledema due to elevated intracranial pressure (ICP) from venous sinus compression. While venous sinus stenting has proven effective for treating elevated intracranial pressure, evidence for its application in tumoral-induced stenosis and acquired intracranial hypertension is limited. This study presents an institutional series of symptomatic tumoral venous sinus stenosis cases and compares the technical considerations of endovascular treatment using a coronary balloon-mounted stent to conventional venous sinus stenting. Three patients with meningioma-induced, bilateral papilledema received treatment with venous sinus stenting between 2019-2022. Presentation, stenosis severity, venous manometry, ophthalmologic findings, procedural techniques, and post-operative outcomes were retrospectively analyzed. Three patients (mean age: 59 years, 2 out of 3 male) presented with worsening blurry vision, diplopia, and persistent headaches. Bilateral papilledema was observed (median optic nerve sheath distension=0.48mm). Pre-procedure measurements showed elevated ICP with opening pressures ranging from 37-38 cmH2O. Imaging revealed extra-axial parieto-occipital lesions with significant mass effect, and MR venograms confirmed severe stenosis of the superior sagittal sinus (SSS). Venous angiography (DSV) demonstrated median venous sinus pressures of 32-mmHg proximal to the stenosis with a 4-mmHg pressure gradient across the stenosis. During the procedure, balloon-mounted Onyx coronary stents or a self-expanding PrecisePro carotid stent were deployed successfully. Post-stenting, papilledema resolved completely in two patients, while one patient experienced partial symptom resolution. Proximal SSS pressures decreased by a mean of 46.8%, and trans-stenotic pressure gradients were reduced to ≤1 mmHg. Stent patency without complications was maintained throughout the 2 to 5-month follow-up in all patients. Adjacent meningiomas were subsequently monitored for observation or stereotactic radiosurgery. Small extra-axial lesions causing symptomatic venous sinus compression can be endovascularly treated using balloon-mounted cardiac stents. Non-surgical meningioma patients, symptomatic for intracranial hypertension and lesions proximal to venous sinuses, should be assessed with DSV for potential management with endovascular interventions.
CTNI-56. FEASIBILITY AND EFFICACY OF AI-GUIDED PERSONALIZED PRECISION RADIATION THERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA: A MATCHED-CONTROL STUDY
Authors: Hamed Akbari, Suyash Mohan, Anahita Fathi Kazerooni, Michel Bilello, Chiharu Sako, Jose Garcia, Cecilia Jiang, Fang Liu, Steven Brem, Spyridon Bakas, Saima Rathore, Elizabeth Mamourian, Abigail Pepin, Paul James, Jay F Dorsey, Ashish Singh, Drew Parker, Ragini Verma, Quy Cao, Russell T Shinohara, Stephen J Bagley, Arati Desai, Donald M O'Rourke, MacLean P Nasrallah, Michelle Alonso-Basanta, Boon-Keng Kevin Teo, Goldie Kurtz, Gaurav Shukla, Robert A Lustig, Christos Davatzikos
Journal: Neuro-Oncology (2023)

Abstract PURPOSE The aim of this study was to evaluate the feasibility and efficacy of AI-guided personalized precision radiation therapy (PPRT) in improving outcomes for patients with newly diagnosed glioblastoma. METHODS In an open-label trial conducted at the University of Pennsylvania (NCT03477513), between August 2018 and April 2021, 17 patients with IDH-wildtype glioblastoma who underwent maximal safe resection were enrolled. They were matched with a cohort of glioblastoma patients based on age, sex, extent of resection (EOR), O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation status, and IDH status. Propensity Score Matching (PSM) was employed to assess the impact of the intervention on the likelihood of survival, using logistic regression to estimate the propensity score. Four patients were disqualified based on exclusion criteria. The PPRT group received personalized radiation dose escalation guided by AI-based predictive modeling of recurrence, along with concomitant and maintenance temozolomide chemotherapy. The control group received standard-of-care chemoradiotherapy between 2012 and 2020. In this study, we utilized a previously published and evaluated (retrospectively and prospectively) predictive AI model, which accurately estimated neoplastic cell infiltration and predicted future tumor recurrence using preoperative, multi-parametric MRIs. RESULTS Median overall survival was 24.4 months in the PPRT-temozolomide group and 17.9 months in the standard-of-care treatment group (hazard ratio, 0.34; 95% CI: 0.15-0.77; p = 0.009). PPRT was well-tolerated, with low-grade adverse events during radiation. Radiation necrosis occurred in 54% of the PPRT-temozolomide group and 36% of the standard-of-care group. CONCLUSION AI-guided PPRT in newly diagnosed glioblastoma patients demonstrated feasibility in routine clinical practice and led to a statistically significant improvement in overall survival compared to matched controls receiving standard-of-care treatment. These findings highlight the potential of personalized precision radiation therapy, with focused dose escalation, in enhancing outcomes for glioblastoma patients and emphasize the need for prospective validation in a randomized controlled clinical trial.
QLTI-02. ADVERSE EVENTS IN GLIOMA SURGERY: RESULTS OF A PROSPECTIVELY COMPILED DATABASE OF A SINGLE-CENTER TERTIARY CARE HOSPITAL
Authors: Philip Dao Trong, Manuel Kaes, Christine Jungk, Andreas Unterberg
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Adverse events in glioma surgery can cause severe problems for patients and can be a significant burden to healthcare systems. Therefore, understanding and avoiding adverse events should be essential in centers performing glioma surgery. Nevertheless, it is still uncommon to assess adverse events in a prospective, standardized manner. In this study we want to share the findings of our prospectively compiled database for adverse events in glioma surgery. METHODS Every patient treated at our institution received a peer-reviewed, standardized discharge form focused on adverse events. Any event, that led to readmission, worsening of clinical outcome, new neurological deficits, revision surgery, contributed to death or prolonged hospital stay within 30 days of discharge was recorded and classified according to the treatment-related classification system of Clavien-Dindo (Grade 1 requiring to treatment to Grade 5 resulting in death). RESULTS In 2022 a total of n = 194 patients received glioma surgery at our institution. Surgery was performed using a common craniotomy in 145 cases (74.7%), an awake craniotomy in 16 cases (8.2%) and in 33 cases (17.0 %) a stereotactic approach for biopsy was chosen. A total of n = 44 (22.7%) adverse events were recorded among these cases. The most common adverse event was a new neurological deficit after surgery in 20 cases (10.3%) followed by non-surgery related adverse events in 10 cases (5.2%). Wound healing disorders and CSF-leaks were recorded in 8 cases (4.1%) and in 6 cases (3.1%), respectively. Clavien Dindo classification showed low-grade complications (grade 1,2) in 15.9% and high-grade complications (grade 3,4,5) in 6.6%. Revision surgery was necessary in 9 cases (4.6%). CONCLUSION Adverse events in glioma surgery are not uncommon. Understanding and classifying these events in a prospective, standardized manner may help to reduce the risk of adverse events in glioma surgery in the future.
CTNI-24. CLINICAL ACTIVITY AND SAFETY OF THE RAF INHIBITOR TOVORAFENIB IN PATIENTS WITH OPTIC PATHWAY GLIOMAS IN THE REGISTRATIONAL PEDIATRIC LOW-GRADE GLIOMA ARM OF THE PHASE 2 FIREFLY-1 (PNOC026) STUDY
Authors: Karsten Nysom, Lindsay Kilburn, Sarah Leary, Daniel Landi, E de Vos-Kerkhof, Sébastien Perreault, Olaf Witt, David Ziegler, Pablo Hernáiz Driever, Andrea Franson, Patricia Baxter, Nicholas S Whipple, Cassie Kline, Devorah Segal, Nada Jabado, Simon Bailey, Geoffrey McCowage, Jordan Hansford, Dong-Anh Khuong-Quang, Nicholas Gottardo, Timothy Hassall, Jung Woo Han, Michal Yalon Oren, Susan Chi, Vai Lee, Lisa McLeod, Jiaheng Qiu, Ashley Walter, Peter Manley, Darren Hargrave
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Optic pathway gliomas (OPG) are low-grade gliomas (LGG) comprising 3-5% of pediatric brain tumors. Morbidity may include visual loss (acuity and visual fields), hypothalamic/pituitary dysfunction, and/or impaired motor function. Genomic alterations of MAPK/BRAF are frequent oncogenic drivers in pediatric LGG. Activity of tovorafenib, an investigational, oral, selective, CNS-penetrant, type II RAF inhibitor in OPGs was analyzed. METHODS FIREFLY-1 (NCT04775485) is a phase 2 study evaluating tovorafenib (420 mg/m2 weekly) in patients 6 months–25 years with BRAF-altered recurrent/progressive LGG or solid tumors. Independently assessed overall response rate (ORR), as defined by RANO-HGG and RANO-LGG criteria, are primary and exploratory endpoints. RESULTS Of the 77 patients enrolled in arm 1 (measurable disease per RANO-HGG), 42 (55%) had tumors located in the optic pathway. Median age at enrollment was 8 years (range: 2–16); 37 (88%) harbored a BRAF fusion and 5 (12%) a BRAF V600E mutation. The median prior lines of systemic therapy was 3 (range: 1–9), with 69% having received prior MAPK inhibitors. Of the 39 evaluable patients (RANO-HGG), the ORR was 59% (1 CR, 22 PRs) with a median time to response (TTR) of 2.8 months; 14 (36%) had stable disease (SD). Per RANO-LGG (n = 42), the ORR was 43% (5 PRs; 13 MRs) with a median TTR of 4.1 months; 20 (48%) had SD. Visual acuity remained stable in 79% (23) of patients (Cycle 9, n = 29 assessed). The most common treatment-related adverse events (TRAEs) of any grade in this subgroup were hair color changes (81%), increased creatine phosphokinase (55%), anemia (48%), maculopapular rash (45%), and fatigue (41%). Dose modifications occurred in 14 (33%) and discontinuations in 3 (7%) patients due to TRAEs. CONCLUSIONS Tovorafenib demonstrated antitumor activity in recurrent/progressive BRAF-altered OPG and was generally well tolerated. Visual acuity remained stable for the majority with OPGs.
MODL-17. OBESOGENIC DIET INCREASES NF1-OPTIC PATHWAY GLIOMA FORMATION THROUGH EFFECTS ON THE TUMOR CELL OF ORIGIN
Authors: Ambrose Chan, Kailong Zhang, Gemma Martin, Sabiha Bano, Wang Avery, Mahto Sarvika, David Gutmann, Nicole Brossier
Journal: Neuro-Oncology (2023)

Abstract Rates of both pediatric low-grade glioma and obesity have been rising in the U.S., and children of obese mothers have increased rates of several tumor types, including brain tumors. Importantly, obesity in the U.S. is largely dietary-driven, given the prevalence of high fat and high sugar (HFHS) diets. High-fat diet exposure can promote proliferation of embryonic neuroglial progenitor cells (NPCs), which animal modeling suggests are potential cells of origin for low-grade glioma. Together, these data suggested that in utero exposure to an obesogenic diet might affect the formation of pediatric brain tumors. Using preclinical models of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, in which optic pathway gliomas (Nf1-OPGs) arise from NPCs in the developing third ventricular zone (TVZ), we sought to determine whether maternal obesogenic exposure would increase glioma formation through intrinsic effects on the tumor cell of origin. We demonstrated that progeny from obese dams exposed to HFHS diet during and preceding gestation had increased proliferation and glial differentiation of WT and Nf1-mutant TVZ NPCs. Progeny of non-obese dams exposed to this diet during gestation demonstrate a similar phenotype, suggesting these effects are related to maternal diet rather than weight. Obesogenic diet exposure (Ob) also increased glioma penetrance in two low-penetrance murine models of Nf1-OPG. Moreover, we demonstrated that Ob mice developed earlier tumor onset with elevated Erk activity in a high-penetrance Nf1-OPG model. In contrast, when obesogenic diet was introduced postnatally, only 11% of mice showed accelerated tumor formation. Ob-exposed nerves also displayed elevated levels of activated Stat3, consistent with upregulation of the IL6/Jak/Stat3 pathway with HFHS diet exposure. These findings establish maternal obesogenic diet as a risk for pediatric glioma formation, in part through in utero effects on the tumor cell of origin, and identify the MAPK and IL6/Jak/Stat3 pathways as targets for further investigation.